This invention relates to a series of heteroaryl-substituted quinolin-2-one derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as agents to combat tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993). The compounds of the present invention exhibit activity as inhibitors of the enzyme farnesyl protein transferase and are therefore believed to be useful as anti-cancer and anti-tumor agents. Further, the compounds of the present invention may be active against any tumors that proliferate by virtue of farnesyl protein transferase.
Other compounds that are indicated as having activity inhibiting farnesyl protein transferase are referred to in International Publication Number WO 97/21701, entitled xe2x80x9cFarnesyl Protein Transferase Inhibiting (Imidazol-5-yl)methyl-2-quinolinone Derivativesxe2x80x9d, which has an International Publication Date of Jun. 19, 1997; in International Publication Number WO 97/16443, entitled xe2x80x9cFarnesyl Transferase Inhibiting 2-Quinolone Derivativesxe2x80x9d, which has an International Publication Date of May 9, 1997; PCT/IB99/01393, filed Aug. 5, 1999, entitled xe2x80x9c2-Quinolone derivatives Useful as Anticancer Agentsxe2x80x9d; and PCT/IB99/01398, filed Aug. 6, 1999, entitled xe2x80x9cAlkynyl-Substituted Quinolin-2-one Derivatives Useful as Anticancer Agentsxe2x80x9d; all of which are incorporated herein by reference in their entireties.
The preceding Kohl et al. publication, as well as all other references discussed below in this application, are also hereby incorporated by reference in their entireties.
The present invention relates to compounds of formula 1
or pharmaceutically acceptable salts or solvates thereof wherein:
the dashed line indicates an optional second bond connecting C-3 and C-4 of the quinolin-2-one ring;
R1 is selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)qC(O)R12, xe2x80x94(CR13R14)qC(O)OR15, xe2x80x94(CR13R14)qOR12, xe2x80x94(CR13R14)qCSO2R15, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R1 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R6 groups;
R2 is halo, cyano, xe2x80x94C(O)OR15, or a group selected from the substituents provided in the definition of R12;
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
R8 is H, xe2x80x94OR12, xe2x80x94OC(O)R12, xe2x80x94NR12R13, xe2x80x94Nxe2x95x90CR12R13, xe2x80x94NR12C(O)R13, cyano, xe2x80x94C(O)OR13, xe2x80x94SR12, or xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein said heterocyclic R8 groups are substituted by 1 to 4 R6 groups;
R9 is xe2x80x94(CR13R14)t(imidazolyl) or xe2x80x94(CR13R14)t(pyridinyl) wherein said imidazolyl or pyridinyl moiety is substituted by 1 or 2 R6 substituents
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5 and each q is independently an integer from 1 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14)q or xe2x80x94(CR13R14)t each is independently defined for each iteration of q or t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H.
Preferred compounds of formula 1 are those wherein Z is a 5 or 6 membered aromatic heterocyclic group substituted with from 1 to 4 R6 substituents. More preferred compounds of formula 1 are those wherein Z is a pyridine or thiophene group substituted with from 1 to 4 R6 substituents. Other preferred compounds of formula 1 are those wherein Z is a 5 or 6 membered aromatic heterocyclic group fused to a benzene group, substituted with from 1 to 4 R6 substituents. Preferably, Z comprises from 1 to 3 heteroatoms selected from O, S and N.
Other preferred compounds of formula 1 are those wherein R1 is H, C1-C6 alkyl, or cyclopropylmethyl.
Other preferred compounds of formula 1 are those wherein R8 is xe2x80x94NR12R13, xe2x80x94OR12, or xe2x80x94(CR13R14)t (4-10 membered heterocyclic) substituted with from 1 to 4 R6 groups, wherein said 4-10 membered heterocyclic is selected from triazolyl, imidazolyl, pyrazolyl, and piperidinyl. More preferably, said heterocyclic is substituted with one R6 group. Preferably, R8 is hydroxy, amino, or triazolyl.
Other preferred compound of formula 1 are those wherein R8 is H, xe2x80x94OR12, xe2x80x94OC(O)R12, xe2x80x94NR12R13, xe2x80x94NR12C(O)R13, cyano, xe2x80x94C(O)OR13, xe2x80x94SR12, or xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein said heterocyclic R8 groups are substituted by I to 4 R6 groups.
Other preferred compounds of formula 1 are those wherein R3, R4, R5 and R6 are independently selected from H, halo, and C1-C6 alkoxy.
Preferred compounds of the invention include:
6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-methyl-1H-quinolin-2-one (enantiomer A);
6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-methyl-1H-quinolin-2-one (enantiomer B);
4-(3-chloro-phenyl)-6-[(6chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one;
6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one;
4-(3-chloro-phenyl)-6-[(5-chloro-pyridin-2-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-1H-quinolin-2-one;
6-[amino-(5-chloro-pyridin-2-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-methyl-1H-quinolin-2-one;
6-[amino-(5-chloro-pyridin-2-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one;
6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3,5-dichloro-phenyl)-1-methyl-1H-quinolin-2-one;
6-[amino-(5-chloro-thiophen-2-yl)-(3-methyl-3H-imidazo-4-yl)-methyl]-4-(3-chloro-phenyl)-1-methyl-1H-quinolin-2-one;
6-[(5-chloro-thiophen-2-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethoxy-phenyl-1-methyl-1H-quinolin-2-one;
amino-(5-chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethoxy-phenyl)-1-methyl-1H-quinolin-2-one;
6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethoxy-phenyl)-1-methyl-1H-quinolin-2-one;
6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethoxy-phenyl)-1-methyl-1H-quinolin-2-one;
6-[benzo[b]thiophen-2-yl-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-methyl-1H-quinolin-2-one;
6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1H-quinolin-2-one;
(xe2x88x92)-6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one;
6-[amino-(6-methyl-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-methyl-1H-quinolin-2-one;
6-[amino-(pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one;
(+)-4-(3-chloro-phenyl)-6-[(6chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one; and
pharmaceutically acceptable salts and solvates of the foregoing compounds.
The present invention also relates to compounds of the formula 12
wherein:
the dashed line indicates an optional second bond connecting C-3 and C-4 of the quinoline ring;
R2 is halo, cyano, xe2x80x94C(O)OR15, or a group selected from the substituents provided in the definition of R12;
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10, alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
R8 is H, xe2x80x94OR12, xe2x80x94OC(O)R12, xe2x80x94NR12R13, xe2x80x94NR12C(O)R13, cyano, xe2x80x94C(O)OR13, xe2x80x94SR12, or xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein said heterocyclic R8 groups are substituted by 1 to 4 R6 groups;
R9 is xe2x80x94(CR13R14)t(imidazolyl) or xe2x80x94(CR13R14)t(pyridinyl) wherein said imidazolyl or pyridinyl moiety is substituted by 1 or 2 R6 substituents;
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14)t each is independently defined for each iteration of t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H.
Compounds of formula 12 are useful as intermediates for preparing compounds of formula 1. Compounds of formula 12 are also prodrugs of compounds of formula 1, and the present invention also includes pharmaceutically acceptable salts and solvates of compounds of formula 12.
The present invention also relates to compounds of the formula 6
wherein:
the dashed line indicates an optional second bond connecting C-3 and C-4 of the quinoline ring;
R2 is halo, cyano, xe2x80x94C(O)OR15, or a group selected from the substituents provided in the definition of R12;
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)R12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
R8 is H, xe2x80x94OR12, xe2x80x94OC(O)R12, xe2x80x94NR12R13, xe2x80x94NR12C(O)R13, cyano, xe2x80x94C(O)OR13, xe2x80x94SR12, or xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein said heterocyclic R8 groups are substituted by 1 to 4 R6 groups;
R9 is xe2x80x94(CR13R14)t(imidazolyl) or xe2x80x94(CR13R14)t(pyridinyl) wherein said imidazolyl or pyridinyl moiety is substituted by 1 or 2 R6 substituents;
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14 )t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14)teach is independently defined for each iteration of t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H.
Compounds of formula 6 are useful as intermediates for preparing compounds of formula 1. Compounds of formula 6 are furthermore prodrugs of compounds of formula 1, and the present invention also includes pharmaceutically acceptable salts and solvates of compounds of formula 6.
The invention also relates to compounds of the formula 2
wherein:
the dashed line indicates an optional second bond connecting C-3 and C-4 of the quinoline ring;
R is C1-C6 alkyl;
R2 is halo, cyano, xe2x80x94C(O)OR15, or a group selected from the substituents provided in the definition of R12;
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
R8 is H, xe2x80x94OR12, xe2x80x94OC(O)R12, xe2x80x94NR12R13, xe2x80x94NR12C(O)R13, cyano, xe2x80x94C(O)OR13, xe2x80x94SR12, or xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein said heterocyclic R8 groups are substituted by 1 to 4 R6 groups;
R9 is xe2x80x94(CR13R14)t(imidazolyl) or xe2x80x94(CR13R14)t(pyridinyl) wherein said imidazolyl or pyridinyl moiety is substituted by 1 or 2 R6 substituents;
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14)t each is independently defined for each iteration of t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H. Compounds of formula 2 are useful as intermediates for preparing compounds of formula 1. Compounds of formula 2 are furthermore prodrugs of compounds of formula 1, and the present invention also includes pharmaceutically acceptable salts and solvates of compounds of formula 2.
This invention also relates to a method of inhibiting abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 1, 2, 12, or 6, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in inhibiting farnesyl protein transferase.
This invention also relates to a method of inhibiting abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula 1, 2, 12, or 6 as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in inhibiting abnormal cell growth.
The invention also relates to a method for the inhibition of abnormal cell growth in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula 1, 2, 12, or 6, or a pharmaceutically acceptable salt or solvate thereof, in combination with a chemotherapeutic. In one embodiment, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
This invention further relates to a method for inhibiting abnormal cell growth in a mammal which method comprises administering to the mammal an amount of a compound of formula 1, 2, 12, or 6, or a pharmaceutically acceptable salt or solvate thereof, in combination with radiation therapy, wherein the amount of the compound, salt, ot solvate of formula 1, 2, 12, or 6 is in combination with the radiation therapy effective in inhibiting abnormal cell growth in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein.
It is believed that the compounds of formula 1, 2, 12, or 6 can render abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of formula 1, 2, 12, or 6, or a pharmaceutically acceptable salt or solvate thereof, which amount is effective in sensitizing abnormal cells to treatment with radiation. The amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
This invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the formula 1, 2, 12, or 6 as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in inhibiting farnesyl protein transferase, and a pharmaceutically acceptable carrier.
This invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the formula 1, 2, 12, or 6 as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in inhibiting abnormal cell growth, and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for the inhibition of abnormal cell growth in a mammal which comprises a therapeutically effective amount of a compound of formula 1, 2, 12, or 6 or a pharmaceutically acceptable salt or solvate thereof, in combination with a chemotherapeutic, and a pharmaceutically acceptable carrier. In one embodiment, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
The invention also relates to a method of and a pharmaceutical composition for treating in a mammal a disease or condition selected from lung cancer, NSCLC (non small cell lung cancer), bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin""s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, iymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), pediatric malignancy, neoplasms of the central nervous system, (e.g., primary CNS lymphoma, spinal axis tumors, brain stem gliomas or pituitary adenomas), Barrett""s esophagus (pre-malignant syndrome), neoplastic cutaneous disease, psoriasis, mycoses fungoides, benign prostatic hypertrophy, human papilloma virus (HPV), and restinosis which comprise an amount of a compound of formula 1, 2, 12, or 6, or a pharmaceutically acceptable salt or solvate of such a compound, that is effective in inhibiting farnesyl protein transferase.
The invention also relates to a method of and pharmaceutical composition for treating in a mammal a disease or condition selected from lung cancer, NSCLC (non small cell lung cancer), bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin""s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), pediatric malignancy, neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumors, brain stem gliomas or pituitary adenomas), Barrett""s esophagus (pre-malignant syndrome), neoplastic cutaneous disease, psoriasis, mycoses fungoides, benign prostatic hypertrophy, human papilloma virus (HPV), and restinosis which comprise an amount of a compound of formula 1, 2, 12, or 6, or a pharmaceutically acceptable salt or solvate of such a compound, that is effective in treating said disease.
This invention also relates to a method of and to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprise an amount of a compound of formula 1, 2, 12, or 6, or a pharmaceutically acceptable salt or solvate thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents, which amounts are together effective in inhibiting abnormal cell growth.
Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, can be used in conjunction with a compound of formula 1, 2, 12, or 6, in the methods and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX(trademark) (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European Patent Application No. 97304971.1 (filed Jul. 8, 1997), European Patent Application No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918 (published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16, 1998), European Patent Publication 606,046 (published Jul. 13, 1994), European Patent Publication 931,788 (published Jul. 28, 1999), WO 90/05719 (published May 331, 1990), WO 99152910 (published Oct. 21, 1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filed Jul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar. 25, 1999), Great Britain patent application number 9912961.1 (filed Jun. 3, 1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued Jan. 19, 1999), and European Patent Publication 780,386 (published Jun. 25, 1997), all of which are incorporated herein in their entireties by reference. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).
Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, RS 13-0830, and the compounds recited in the following list:
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic acid;
3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide;
(2R, 3R) 1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cydobutyl)-amino]-propionic acid;
4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic acid hydroxyamide;
(R) 3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid hydroxyamide;
(2R, 3R) 1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionic acid;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyi-tetrahydro-pyran-4-yl)-amino3-propionic acid;
3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide;
3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic acid hydroxyamide; and
(R) 3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic acid hydroxyamide;
and pharmaceutically acceptable salts and solvates of said compounds.
Other anti-angiogenesis agents, including other COX-II inhibitors and other MMP inhibitors, can also be used in the present invention.
A compound of formula 1, 2, 12, or 6, can also be used with signal transduction inhibitors, such as agents that can inhibit EGFR (epidermal growth factor receptor) responses, such as EGFR antibodies, EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascular endothelial growth factor) inhibitors; and erbB2 receptor inhibitors, such as organic molecules or antibodies that bind to the erbB2 receptor, for example, HERCEPTIN(trademark) (Genentech, Inc. of South San Francisco, Calif., USA).
EGFR inhibitors are described in, for example in WO 95/19970 (published Jul. 27, 1995), WO 98114451 (published Apr. 9, 1998), WO 98/02434 (published Jan. 22, 1998), and U.S. Pat. No. 5,747,498 (issued May 5, 1998), and such substances can be used in the present invention as described herein. EGFR-inhibiting agents include, but are not limited to, the monoclonal antibodies C225 and anti-EGFR 22Mab (ImClone Systems Incorporated of New York, N.Y., USA), the compounds ZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc. of Annandale, N.J., USA), and OLX-103 (Merck and Co. of Whitehouse Station, N.J., USA), VRCTC-310 (Ventech Research) and EGF fusion toxin (Seragen Inc. of Hopkinton, Mass.). These and other EGFR-inhibiting agents can be used in the present invention.
VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif., USA), can also be combined with a compound of formula 1, 2, 12, or 6. VEGF inhibitors are described in, for example in WO 99124440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17, 1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 98/50356 (published Nov. 12, 1998), U.S. Pat. No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issued Mar. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), WO 99/10349 (published Mar. 4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596 (published Jun. 26, 1997), WO 98154093 (published Dec. 3, 1998), WO 98/02438 (published Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO 98/02437 (published Jan. 22, 1998), all of which are incorporated herein in their entireties by reference. Other examples of some specific VEGF inhibitors useful in the present invention are IM862 (Cytran Inc. of Kirkland, Wash., USA); anti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, Calif.; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.). These and other VEGF inhibitors can be used in the present invention as described herein.
ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), can furthermore be combined with a compound of formula 1, 2, 12, or 6, for example those indicated in WO 98/02434 (published Jan. 22, 1998), WO 99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2, 1999), which are all hereby incorporated herein in their entireties by reference. ErbB2 receptor inhibitors useful in the present invention are also described in U.S. Provisional Application No. 60/117,341, filed Jan. 27, 1999, and in U.S. Provisional Application No. 60/117,346, filed Jan. 27,1999, both of which are incorporated in their entireties herein by reference. The erbB2 receptor inhibitor compounds and substance described in the aforementioned PCT applications, U.S. patents, and U.S. provisional applications, as well as other compounds and substances that inhibit the erbB2 receptor, can be used with a compound of formula 1, 2, 12, or 6, in accordance with the present invention.
A compound of formula 1, 2, 12, or 6, can also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocite antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors described in the references cited in the xe2x80x9cBackgroundxe2x80x9d section, supra. Specific CTLA4 antibodies that can be used in the present invention include those described in U.S. Provisional Application 60/113,647 (filed Dec. 23, 1998) which is incorporated by reference in its entirety, however other CTLA4 antibodies can be used in the present invention.
The invention also relates to compounds of the formula 13
wherein:
the dashed line indicates an optional second bond connecting C-3 and C-4 of the quinolin-2-one ring;
W is selected from fluoro, chloro, bromo, and iodo;
R1 is selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)qC(O)R12, xe2x80x94(CR13R14)qC(O)OR15, xe2x80x94(CR13R14)qOR12, xe2x80x94(CR13R14)qCSO2R15, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R1 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R6 groups;
R2 is halo, cyano, xe2x80x94C(O)OR15, or a group selected from the substituents provided in the definition of R12;
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
R9 is xe2x80x94(CR13R14)t(imidazolyl) or xe2x80x94(CR13R14)t(pyridinyl) wherein said imidazolyl or pyridinyl moiety is substituted by 1 or 2 R6 substituents;
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5 and each q is independently an integer from 1 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94CR13R14)q or xe2x80x94(CR13R14)t each is independently defined for each iteration of q or t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H. Compounds of formula 13 are useful as intermediates for preparing compounds of formula 1.
The invention also relates to compounds of the formula 29
wherein:
R is C1-C6 alkyl;
R2 is halo, cyano, xe2x80x94C(O)OR15, or a group selected from the substituents provided in the definition of R12;
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t (4-10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR3R_4)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14) each is independently defined for each iteration t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H. Compounds of formula 29 are useful as intermediates for preparing compounds of formula 1.
The invention also relates to compounds of the formula 30
wherein:
R1 is selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)qC(O)R12, xe2x80x94(CR13R14)qC(O)OR15, xe2x80x94(CR13R14)qOR12, xe2x80x94(CR13R14)qCSO2R15, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R1 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R6 groups;
R2 is halo, cyano, xe2x80x94C(O)OR15, or a group selected from the substituents provided in the definition of R12;
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5 and each q is independently an integer from 1 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14)q or xe2x80x94(CR13R14)t each is independently defined for each iteration of q or t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H. Compounds of formula 30 are useful as intermediates for preparing compounds of formula 1.
The invention also relates to compounds of the formula 26
wherein:
R24 is selected from xe2x80x94SR20 and xe2x80x94SiR21R22R23, wherein R20 is selected from H and phenyl, and R21, R22, and R23 are independently selected from C1-C6 alkyl and phenyl;
R1 is selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)qC(O)R12, xe2x80x94(CR13R14)qC(O)OR15, xe2x80x94(CR13R14)qOR12, xe2x80x94(CR13R14)qCSO2R15, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic), wherein said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R1 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R6 groups;
R2 is halo, cyano, xe2x80x94C(O)OR15, or a group selected from the substituents provided in the definition of R12;
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13 xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5 and each q is independently an integer from 1 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14)q or xe2x80x94(CR13R14)t each is independently defined for each iteration of q or t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H. Compounds of formula 26 are useful as intermediates for preparing compounds of formula 1.
The invention also relates to a method of synthesizing a compound of the formula 
wherein
R6 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C6 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14)t each is independently defined for each iteration of t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H;
which method comprises reacting in an appropriate solvent in the presence of a suitable base a compound of the formula 
wherein Z is as defined above;
with a compound of the formula 
wherein R6 is as defined above, and
R21, R22, and R23 are each independently selected from C1-C6 alkyl and phenyl;
thereby obtaining a compound of the formula 
and reacting the compound of formula 32 so obtained in an appropriate solvent with acetic acid or with a fluoride reagent. Said method can be used in preparing compounds of formula 1.
The invention also relates to a method of synthesizing a compound of the formula 
wherein
R6 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C10 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14)t each is independently defined for each iteration of t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H;
which method comprises reacting in an appropriate solvent in the presence of a suitable base a compound of the formula 
wherein Z is as defined above;
with a compound of the formula 
wherein R6 is as defined above and R20 is selected from H and phenyl;
thereby obtaining a compound of the formula 
and removing from the compound of formula 31 so obtained the xe2x80x94SR20 group, either:
a) reductively, with a nickel catalyst; or
b) oxidatively, with nitric acid or with aqueous hydrogen peroxide in acetic acid. Said method can be used in preparing compounds of formula 1.
The invention also relates to a method of synthesizing a compound of the formula 
wherein
each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)Cxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14 )t each is independently defined for each iteration of t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19R; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H;
which method comprises reacting, at a temperature of from about xe2x88x9278xc2x0 C. to about 0xc2x0 C., in the presence of a suitable base and in an appropriate solvent a compound of formula 
wherein W is an appropriate leaving group, and R3, R4 and R5 are as defined above, with a compound of the formula 
wherein R6 and R7 are as defined above. Said method can be used in preparing compounds of formula 1. In a preferred embodiment of the above-described method for synthesizing a compound of formula 23, the solvent in which the compound of formula 34 and the compound of formula 35 are reacted is ethyl ether.
The invention also pertains to a method of synthesizing a compound of the formula 
wherein R6 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14R)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
which method comprises
a) reacting with a metal cyanide, in the presence of a palladium catalyst and in an appropriate solvent, at a temperature of about 25xc2x0 C. to about 100xc2x0 C., a compound of the formula 
wherein Tf is xe2x80x94SO2-CF3 and R6 is as defined above;
thereby obtaining a compound of the formula 37. This method is useful in the preparation of compounds of formula 1.
In one embodiment of the method described in the immediately preceding paragraph, a compound of the formula 
is further synthesized, wherein
R6 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94OR12, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94NR13C(O)OR15, xe2x80x94OC(O)R12, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94CHxe2x95x90NOR12, xe2x80x94S(O)jR12 wherein j is an integer from 0 to 2, xe2x80x94(CR13R14)t(C6-C10 aryl), xe2x80x94(CR13R14)t(4-10 membered heterocyclic), xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), and xe2x80x94(CR13R14)tCxe2x89xa1CR16; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94NR13SO2R15, xe2x80x94SO2NR12R13, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)Rw2, xe2x80x94NR13C(O)OR15, xe2x80x94NR13C(O)R12, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, xe2x80x94OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic);
each R12 is independently selected from H, C1-C10 alkyl, xe2x80x94(CR13R14)t(C3-C10 cycloalkyl), xe2x80x94(CR13R14)t(C6-C10 aryl), and xe2x80x94(CR13R14)t(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R12 substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, xe2x80x94C(O)R13, xe2x80x94C(O)OR13, xe2x80x94OC(O)R13, xe2x80x94NR13C(O)R14, xe2x80x94C(O)NR13R14, xe2x80x94NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each t is independently an integer from 0 to 5;
each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as xe2x80x94(CR13R14) each is independently defined for each iteration of t in excess of 1;
R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
R16 is selected from the list of substituents provided in the definition of R12 and xe2x80x94SiR17R18R19; and,
R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H;
which embodiment comprises
a) reacting with a metal cyanide, in the presence of a palladium catalyst and in an appropriate solvent, at a temperature of about 25xc2x0 C. to about 100xc2x0 C., a compound of the formula 
wherein Tf is xe2x80x94SO2-CF3 and R6 is as defined above;
thereby obtaining a compound of the formula 
b) treating the compound of formula 37 so obtained with either a suitable base or a suitable acid under hydrolysis conditions;
thereby obtaining a compound of the formula 
wherein Y is OH;
c) converting the compound of formula 38 so obtained to a compound of the formula 
wherein Y is xe2x80x94Cl or N1-imidazole; and
d) treating the compound of formula 38 obtained in (c) with N,O-dimethyihydroxyamine, in the presence of a suitable base and in an appropriate solvent, at a temperature of from about 0xc2x0 C. to about 40xc2x0 C. Said embodiment can also be used in preparing compounds of formula 1.
xe2x80x9cAbnormal cell growthxe2x80x9d, as used herein, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes, but is not limited to, the abnormal growth of: (1) tumor cells (tumors), both benign and malignant, expressing an activated Ras oncogene; (2) tumor cells, both benign and malignant, in which the Ras protein is activated as a result of oncogenic mutation in another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs. Examples of such benign proliferative diseases are psoriasis, benign prostatic hypertrophy, human papilloma virus (HPV), and restinosis. xe2x80x9cAbnormal cell growthxe2x80x9d also refers to and includes the abnormal growth of cells, both benign and malignant, resulting from activity of the enzyme farnesyl protein transferase.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein, unless otherwise indicated, includes cyclic alkyl moieties wherein alkyl is as defined above. Multicyclic, such as bicyclic and tricyclic, groups are included in this definition.
The term xe2x80x9calkenylxe2x80x9d, as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbonxe2x80x94carbon double bond wherein alkyl is as defined above.
The term xe2x80x9calkynylxe2x80x9d, as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbonxe2x80x94carbon triple bond wherein alkyl is as defined above. Examples of alkynyl groups include, but are no limited to, ethynyl and 2-propynyl.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term xe2x80x9cheterocyclicxe2x80x9d, as used herein, unless otherwise indicated, means aromatic and non-aromatic heterocyclic groups (including saturated heterocyclic groups) containing one or more heteroatoms each selected from O, S and N, wherein each ring of a heterocyclic group has from 4 to 10 atoms. Non-aromatic heterocyclic groups may include rings having only 4 atoms, but aromatic heterocyclic rings must have at least 5 atoms. Heterocyclic groups of this invention unless otherwise indicated may contain one ring or more than one ring, i.e. they may be monocyclic or multicyclic, for example bicyclic (which may comprise non-aromatic and/or aromatic rings). Preferably, bicyclic heterocyclic groups of this invention contain 6-9 members in their ring systems. Monocyclic heterocyclic groups of this invention preferably contain 5 or 6 members. Aromatic multicyclic heterocyclic groups include benzo-fused ring systems. The heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties. An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the compounds listed above, may be C-attached or N-attached where such is possible. For 4 instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
Where R13 and R14 are as (CR13R14)q or (CR13R14)t, each R13 and R14 is independently defined for each iteration of q or t in excess of 1. This means, for instance, that where q or t is 2 alkylene moieties of the type xe2x80x94CH2CH(CH3)-xe2x80x94and other asymmetrically branched groups, are included.
The term xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of formula 1. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of carboxylic acid groups and hydrochloride salts of amino groups. Other pharmaceutically acceptable salts of amino groups are hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. The preparation of such salts is described below.
Certain compounds of formula 1 may have asymmetric centers and therefore exist in different enantiomeric forms. Ali optical isomers and stereoisomers of the compounds of formula 1, and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula 1, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of formula 1 may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
The subject invention also includes prodrugs of compounds of formula 1, which prodrugs are derivatives of compounds of formula 1, which compounds comprise free amino groups, said derivatives comprising amide, carbamide, or peptide derivations of said amino groups. Such prodrugs can comprise an amino acid residue, or a polypeptide chain of two or more, such as up to four, amino acid residues, that are covalently joined through peptide bonds. Amino acid residues useful in preparing prodrugs of the invention include the 20 naturally-occurring amino acids designated by three letter symbols, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, omithine and methionine sulfone. Preferred amino acid residues are those with a non-polar group such as Ala, Val, Nval, Leu, Met, Gly, Pro, Phe, or a basic polar group such as Lys.
The subject invention also includes prodrugs of compounds of formula 1, which prodrugs are the compounds of formula 2, formula 12 and the compounds of formula 6 described herein.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 13H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula 1 of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
Patients that can be treated with a compound of formula 1, 2, 6, or 12, or a pharmaceutically acceptable salt or solvate thereof, according to the methods of this invention include, for example, patients that have been diagnosed as having lung cancer, NSCLC (non small cell lung cancer), bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin""s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), pediatric malignancy, neoplasms of the central nervous system (e.g., primary CNS lymphoma, spinal axis tumors, brain stem gliomas or pituitary adenomas), neoplastic cutaneous diseases (e.g. psoriasis, mycoses fungoides), or Barrett""s esophagus (pre-malignant syndrome).
The compounds of formula 1, 2, 12, and 6, and their pharmaceutically acceptable salts and solvates can each independently also furthermore be used in a palliative neo-adjuvantladjuvant therapy in alleviating the symptoms associated with the diseases recited in the preceding paragaph as well as the symptoms associated with abnormal cell growth. Such, therapy can be a monotherapy or can be in a combination with chemotherapy and/or immunotherapy.
Patients that can be treated according to the methods of this invention also include patients suffering from abnormal cell growth, as defined above.
In the following Schemes and Examples, xe2x80x9cEtxe2x80x9d represents an ethyl moiety, and xe2x80x9cMexe2x80x9d represents a methyl moiety. Hence, for example, xe2x80x9cOEtxe2x80x9d means ethanol. Also, xe2x80x9cTHFxe2x80x9d means tetrahydrofuran, and xe2x80x9cDMFxe2x80x9d means dimethylformamide.
The compounds of formula 1 may be prepared as described below.
With reference to Scheme 1 below, the compounds of formula 1 may be prepared by hydrolysing an intermediate ether of formula 2, wherein R is C1-C6 alkyl, according to methods familiar to those skilled in the art, such as by stirring the intermediate of formula 2 in an aqueous acid solution. An appropriate acid is, for example, hydrochloric acid. The resulting quinolinone of formula 1 wherein R1 is hydrogen may be transformed into a quinolinone wherein R1 has a meaning as defined above apart from hydrogen by N-alkylation methods familiar to those skilled in the art. 
With reference to Scheme 2 below, the intermediate of formula 2, referred to above, may be prepared by reacting an intermediate of formula 10, wherein W is an appropriate leaving group, such as halo, with an intermediate ketone of formula 11. This reaction is done by converting the intermediate of formula 10 into a organometallic compound, by stirring it with a strong base such as butyl lithium, and subsequently adding the intermediate ketone of formula 11. Although this reaction gives at first instance a hydroxy derivative (R8 is hydroxy), said hydroxy derivative can be converted into other intermediates wherein R8 has another definition by performing functional group transformations familiar to those skilled in the art. 
With reference to Scheme 3 below, compounds of formula 36, which are compounds of formula 1 wherein the dotted line is a bond and R1 is hydrogen, can be prepared via ring opening of the isoxazole moiety of the intermediate of formula 22 by stirring it with an acid, such as TiCl3, in the presence of water. Subsequent treatment of the resulting intermediate of formula 23 with a suitable reagent, such as R2CH2COCl or R2CH2COOC2H5, wherein R is as defined above, yields either directly a compound of formula 36 or an intermediate which can be converted to a compound of formula 36 by treatment with a base, such as potassium tert-butoxide. The intermediate of formula 36 can be converted to intermediate of formula 10 by stirring it with an o-alkylation reagent, such as trimethyloxonium tetrafluoroborate (BF4OMe3) for a period of time, typically 4 to 15 hours, and subsequently adding a strong base such as sodium hydroxide in aqueous. 
With reference to Scheme 4 below, compounds of formula 1 wherein R8 is a radical of formula xe2x80x94NR12R13 wherein R12 and R13 are as described above (said compounds are represented below by formula 1(g)), may be prepared by reacting an intermediate of formula 13, wherein W is an appropriate leaving group, such as halo, with a reagent of formula 14. Said reaction may be performed by stirring the reactants in an appropriate solvent, such as THF. 
Compounds of formula 1(g), or other embodiments of formula 1, wherein the dotted line represents a bond can be converted into compounds wherein the dotted line does not represent a bond by hydrogenation methods familiar to those skilled in the art. Compounds wherein the dotted line does not represent a bond may be converted into compounds wherein the dotted line represents a bond by oxidation methods familiar to those skilled in the art.
With reference to Scheme 5 below, compounds of formula 1 wherein R8 is hydroxy (said compounds being represented by formula 1(b)) may be converted into compounds of formula 1(c), wherein R12 has the meaning described above except it is not hydrogen, by methods known to those skilled in the art, including O-alkylation or O-acylation reactions; such as by reacting the compound of formula 1(b) with an alkylating reagent such as R12-W, wherein R12 is as described above, in appropriate conditions, such as in a dipolar aprotic solvent, such as DMF, in the presence of a base, such as sodium hydride. W is a suitable leaving group, such as a halo group or a sulfonyl group. 
As an alternative to the above reaction procedure, compounds of formula 1(c) may also be prepared by reacting a compound of formula 1(b) with a reagent of formula R12-OH, wherein R12 is as described above, in acidic medium.
Compounds of formula 1(b) may also be converted into compounds of formula 1(g), wherein R12 is hydrogen and R13 is replaced with C1-C6 alkyloarbonyl, by reacting compounds of formula 1(b) in acidic medium, such as sulfuric acid, with C1-C6 alkyl-CN in a Ritter-type reaction. Further, compounds of formula 1(b) may also be converted into compounds of formula 1(g), wherein R12 and R13 are hydrogen, by reacting a compound of formula 1(b) with ammonium acetate and subsequent treatment with NH3(aq.).
With reference to Scheme 6 below, compounds of formula 1(b), referred to above, may also be converted into compounds of formula 1(d), wherein R8 is hydrogen, by submitting a compound of formula 1(b) to appropriate reducing conditions, such as stirring in trifluoroacetic acid in the presence of an appropriate reducing agent, such as sodium borohydride, or, alternatively, stirring the compound of formula 1(b) in acetic acid in the presence of formamide. Further, the compound of formula 1(d) wherein R8 is hydrogen may be converted into a compound of formula 1(e) wherein R12 is C1-C10 alkyl by reacting the compound of formula 1(d) with a reagent of formula 5, wherein W is an appropriate leaving group, in an appropriate solvent, such as diglyme, in the presence of a base, such as potassium tert-butoxide. 
With reference to Scheme 7 below, compounds of formula 1 may be prepared by reacting a nitrone of formula 6 with the anhydride of a carboxylic acid, such as acetic anhydride, thus forming the corresponding ester on the 2-position of the quinoline moiety. Said quinoline ester can be hydrolyzed in situ to the corresponding quinolinone using a base, such as potassium carbonate. 
Alternatively, compounds of formula 1 can be prepared by reacting a nitrone of formula 6 with a sulfonyl containing electrophilic reagent, such as ptoluenesulfonylchloride, in the presence of a base, such as aqueous potassium carbonate. The reaction initially involves the formation of a 2-hydroxy-quinoline derivative which is subsequently tautomerized to the desired quinolinone derivative. The application of conditions of phase transfer catalysis, which are familiar to those skilled in the art, may enhance the rate of the reaction.
Compounds of formula 1 may also be prepared by an intramolecular photochemical rearrangement of compounds of formula 6, referred to above. Said rearrangement can be carried out by dissolving the reagents in a reaction-inert solvent and irradiating at a wavelength of 366 nm. It is advantageous to use degassed solutions and to conduct the reaction under an inert atmosphere, such as oxygen-free argon or nitrogen gas, in order to minimize undesired side reactions or reduction of quantum yield.
The substituents of the compounds of formula 1 may be converted to other substituents falling within the scope of formula 1 via reactions or functional group transformations familiar to those skilled in the art. A number of such transformations are already described above. Other examples are hydrolysis of carboxylic esters to the corresponding carboxylic acid or alcohol; hydrolysis of amides to the corresponding carboxylic acids or amines; hydrolysis of nitrites to the corresponding amides; amino groups on imidazole or phenyl moieties may be replaced by hydrogen by diazotation reactions familiar to those skilled in the art, and subsequent replacement of the diazo-group by hydrogen; alcohols may be converted into esters and ethers; primary amines may be converted into secondary or tertiary amines; double bonds may be hydrogenated to the corresponding single bond.
With reference to Scheme 8 below, intermediates of formula 29, wherein R is, as defined above, C1-C6 alkyl, may be prepared by reacting an intermediate of formula 10 with an intermediate of formula 28, or a functional derivative thereof, under appropriate conditions. This reaction is done by converting the intermediate of formula 10 into an organometallic compound, by stirring it with a strong base such as butyl lithium, and subsequently adding the intermediate amide of formula 28. 
With reference to Scheme 9 below, the intermediate nitrones of formula 6 can be prepared by N-oxidizing a quinoline derivative of formula 12 with an appropriate oxidizing agent, such as m-chloro-peroxybenzoic acid or H2O2, in an appropriate solvent, such as dichloromethane.
Said N-oxidation may also be carried out on a precursor of a quinoline of forumula 12.
The intermediate of formula 12 may be metabolized in vivo into compounds of formula 1 via intermediates of formula 6. Hence, intermediates of formula 12 and 6 can act as prodrugs of compounds of formula 1. Also, the intermediates of formula 2 can be metabolized in vivo to compounds of formula 1. Hence, compounds of formula 2 are deemed xe2x80x9cprodrugsxe2x80x9d for puposes of the present invention. Such prodrugs are within the scope of the present invention. 
With reference to Scheme 10 below, the compound of formula 30 can be prepared by hydrolysing an intermediate formula 29, wherein R is C1-C6 alkyl, according to methods familiar to those skilled in the art, such as by stirring the intermediate of formula 29 in an aqueous acid solutori or in an organic solvent with the presence of a Lewis acid. An appropriate acid is, for example, hydrochloric acid. An appropriate Lewis acid and the solvent are, for example, iodotrimethylsilane and dicholoromethane. The resulting quinolinone of formula 30 wherein R1 is hydrogen may be transformed into a quinolinone wherein R1 has a meaning as defined above apart from hydrogen by N-alkylation methods familiar to those skilled in the art. 
With reference to Scheme 11 below, the compound of formula 26 can be prepared by reacting a compound of formula 30 with an intermediate of formula 27, where R24 is SR20 or SiR21R22R23, R20 being H or phenyl, and R21, R22, and R23 being independently selected from C1-C6 alkyl and phenyl. This reaction requires the presence of a suitable base, such as tert-butyl lithium (when R24 is SR20 and R20=H) or lithium 2,2,6,6,-tetramethylpiperidine (when R24 is SR20 and R20=phenyl), or n-butyl lithium (when R24 is SiR21R22R23), in an appropriate solvent, such as THF. The xe2x80x94SR20 group can be reductively removed from the compound of formula 26 with a nickel catalyst such as RANEY(trademark) nickel or oxidatively with nitric acid or aqueous hydrogen peroxide in acetic acid. When R24 is SiR21R22R23, then R24 can be removed from the compound of formula 26 by reaction with acetic acid or a fluoride reagent such as tetrabutylammonia fluoride (TBAF) in a solvent such as tetrahydrofuran. Thus, a compound of formula 1 can be synthesized. 
With reference to Scheme 12, intermediates of formula 11a, which are compounds of formula 11 wherein R9 is imidazole substituted with R6, wherein R6 is as defined above, can be prepared by reacting an intermediate of formula 28 with an intermediate of formula 27 where R21, R22, R23 are C1-C6 alkyl or phenyl to generate an intermediate of formula 32. This reaction requires the presence of a suitable base, such as n-butyl lithium, in an appropriate solvent, such as THF. The intermediate of formula 32 is reacted with acetic acid or a fluoride reagent such as TBAF in a solvent such as tetrahydrofuran to obtain the compound of formula 11a. Alternatively, the compound of formula 11a can be prepared by reacting a compound of formula 28 with an intermediate of formula 27 where R20 is H or phenyl. This reaction requires the presence of a suitable base, such as tert-butyl lithium (when R20=H) or lithium 2,2,6,6,-tetramethylpiperidine (when R20=phenyl), in an appropriate solvent, such as THF. The xe2x80x94SR20 group can be reductively removed from the compound of formula 31 with a nickel catalyst such as RANEY(trademark) nickel or oxidatively with nitric acid or aqueous hydrogen peroxide in acetic acid. 
With reference to Scheme 13, intermediates of formula 23 may also be synthesized by reacting an intermediate of formula 34, wherein W is an appropriate leaving group, such as halo, with an intermediate amide of formula 35. This reaction requires the presence of a suitable base, such as n-butyl lithium, in an appropriate solvent, such as diethyl ether at a temperature of from about xe2x88x9278 to about zero degrees C. 
With reference to Scheme 14, intermediates of formula 28a, which are compounds of formula 28 wherein Z is a pyridine substituted with R6, can be prepared by reacting an intermediate of formula 36 with a metal cyanide, such as Zn(CN)2 or NaCN, in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)-palladium, in an appropriate solvent, such as THF or DMF, at a temperature of from about 25 to about 100 degrees C. Subsequent treatment of the resulting intermediate of formula 37 with either a base or acid under hydrolysis conditions familiar to those skilled in the art, yields a compound of formula 38a which are compounds of formula 38 wherein Y is xe2x80x94OH. The intermediate of formula 38 can be converted to its activated form, intermediate 38b which are compounds of formula 38 wherein Y is xe2x80x94Cl or N1-imidazole using methods familiar to those skilled in the art. Subsequent conversion to 28a is furnished with N,O-dimethylhydroxyamine in the presence of a base, such as triethylamine, pyridine, or 4-dimethyaminopyridine, in an appropriate solvent, such as dichloromethane at a temperature of from about zero to about 40 degrees C. In Scheme 14, xe2x80x9cTfxe2x80x9d represents trifluoromethanesulfonyl, i.e., xe2x80x94SO2-CF3. 
The compounds of formula 1 and some of the intermediates described above may have one or more stereogenic centers in their structure. Such stereogenic centers may be present in a R or a S configuration. Oxime moieties, such as where R3, R4, R5, R6 or R7 is xe2x80x94CHxe2x95x90NOR12, may exist in E or Z configurations.
The compounds of formula 1 as prepared in the above processes are generally racemic mixtures of enantiomers which can be separated from one another following resolution procedures familiar to those skilled in the art. The racemic compounds of formula 1 may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomerics forms of the compounds of formula 1 involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs sterospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecfic methods of preparation. These methods will advantageously employ enantiomerigally pure starting materials.
The compounds of formula 1 that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula 1 from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is readily obtained. The desired acid addition salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid. Cationic salts of the compounds of formula 1 are similarly prepared except through reaction of a carboxy group with an appropriate cationic salt reagent, such as sodium, potassium, calcium, magnesium, ammonium, N,Nxe2x80x2-dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine, tromethamine, or diethanolamine.
The compounds of formula 1, 12, and 6 and their pharmaceutically acceptable salts and solvates (hereinafter referred to, collectively, as xe2x80x9cthe therapeutic compoundsxe2x80x9d) can be administered orally, transdermally (e.g., through the use of a patch), parenterally or topically. Oral administration is preferred. In general, compounds of the formula 1, 12, and 6 and their pharmaceutically acceptable salts and solvates are most desirably administered in dosages ranging from about 1.0 mg up to about 500 mg per day, preferably from about 1 to about 100 mg per day in single or divided (i.e., multiple) doses. The therapeutic compounds will ordinarily be administered in daily dosages ranging from about 0.01 to about 10 mg per kg body weight per day, in single or divided doses. Variations may occur depending on the weight and condition of the person being treated and the particular route of administration chosen. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
The therapeutic compounds may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the two routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic compounds of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions andlor elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a therapeutic compound in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
Additionally, it is also possible to administer the therapeutic compounds topically and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The therapeutic compounds may also be administered to a mammal other than a human. The dosage to be administered to a mammal will depend on the animal species and the disease or disorder being treated. The therapeutic compounds may be administered to animals in the form of a capsule, bolus, tablet or liquid drench. The therapeutic compounds may also be administered to animals by injection or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. As an alternative the therapeutic compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
For the combination therapies and pharmaceutical compositions described herein, the effective amounts of the compound of the invention and of the chemotherapeutic or other agent useful for inhibiting abnormal cell growth (e.g., other antiproliferative agent, anti-agiogenic, signal transduction inhibitor or immune-system enhancer) can be determined by those of ordinary skill in the art, based on the effective amounts for the compound described herein and those known or described for the chemotherapeutic or other agent. The formulations and routes of administration for such therapies and compositions can be based on the information described herein for compositions and therapies comprising the compound of the invention as the sole active agent and on information provided for the chemotherapeutic or other agent in combination therewith.
The compounds of formula 1 exhibit activity as Ras farnesylation inhibitors and are useful in the treatment of cancer and the inhibition of abnormal cell growth in mammals, including humans. The activity of the compounds of formula 1 as Ras farnesylation inhibitors may be determined by their ability, relative to a control, to inhibit Ras farnesyl transferase in vitro. An example of one such procedure is described below.
A crude preparation of human farnesyl transferase (FTase) comprising the cytosolic fraction of homogenized brain tissue is used for screening compounds in a 96-well assay format. The cytosolic fraction is prepared by homogenizing approximately 40 grams of fresh tissue in 100 ml of sucrose/MgCl2/EDTA buffer (using a Dounce homogenizer; 10-15 strokes), centrifuging the homogenates at 1000 g for 10 minutes at 4xc2x0 C., re-centrifuging the supernatant at 17,000 g for 15 minutes at 4xc2x0 C., and then collecting the resulting supematant. This supernatant is diluted to contain a final concentration of 50 mM Tris HCl (pH 7.5), 5 mM DTT, 0.2 M KCl, 20 xcexcM ZnCl2, 1 mM PMSF and re-centrifuged at 178,000 g for 90 minutes at 4xc2x0 C. The supernatant, termed xe2x80x9ccrude FTasexe2x80x9d is assayed for protein concentration, aliquoted, and stored at xe2x88x9270xc2x0 C.
The assay used to measure in vitro inhibition of human FTase is a modification of the method described by Amersham LifeScience for using their Farnesyl transferase (3H) Scintillation Proximity Assay (SPA) kit (TRKQ 7010). FTase enzyme activity is determined in a volume of 100 xcexcl containing 50 mM N-(2-hydroxy ethyl) piperazine-N-(2-ethane sulfonic acid) (HEPES), pH 7.5, 30 mM MgCl2, 20 mM KCl, 25 mM Na2HPO4, 5 mM dithiothreitol (DTT), 0.01% Triton X-100, 5% dimethyl sulfoxide (DMSO), 20 mg of crude FTase, 0.12 mM [3H]-farnesyl pyrophosphate ([3H]-FPP; 36000 dpm/pmole, Amersham LifeScience), and 0.2 xcexcM of biotinylated Ras peptide KTKCVIS (Bt-KTKCVIS) that is N-terminally biotinylated at its alpha amino group and was synthesized and purified by HPLC in house. The reaction is initiated by addition of the enzyme and terminated by addition of EDTA (supplied as the STOP reagent in kit TRKQ 7010) following a 45 minute incubation at 37xc2x0 C. Prenylated and unprenylated Bt-KTKCVIS is captured by adding 150 xcexcl of steptavidin-coated SPA beads (TRKQ 7010) per well and incubating the reaction mixture for 30 minutes at room temperature. The amount of radioactivity bound to the SPA beads is determined using a MicroBeta 1450 plate counter. Under these assay conditions, the enzyme activity is linear with respect to the concentrations of the prenyl group acceptor, Bt-KTKCVIS, and crude FTase, and inhibition of Bt-KTKCVIS interaction with FTase can be detected. The enzyme activity is saturating with respect to the prenyl donor, FPP. The assay reaction time is also in the linear range.
The test compounds are routinely dissolved in 100% DMSO. Inhibition of farnesyl transferase activity is determined by calculating percent incorporation of tritiated-farnesyl in the presence of the test compound versus its incorporation in control wells (absence of inhibitor). IC50 values, that is, the concentration required to produce half maximal farnesylation of Bt-KTKCVIS, is determined from the dose-responses obtained.
All of the title compounds of formula 1 in the following Examples were assayed for their ability to inhibit the activity of human farnesyl transferase in vitro using the assay described above, and were found to have IC50 values for inhibiting farnesylation of the biotinylated KTKCVIS-peptide of about less than or equal to 500 nM.